Elucidating the Mechanism of Amyloid Formation by Human Lysozyme

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Our bodies contain some 100,000 proteins that enable or regulate essentially every chemical or biochemical process on which our lives depend. Under normal circumstances these proteins remain in their soluble functional states, but under other circumstances, for example as a result of mutations or even the impairment of regulating processes, they can form large insoluble aggregates that are non-functional and even toxic. This process is of great importance because it is the underlying origin of a range of debilitating human disorders, including neurodegenerative conditions such as Alzheimer's disease, the transmissible spongiform encephalopathies (such as CJD, the human analogue of 'mad cow disease'), type 2 (late onset) diabetes and systemic pathologies in which large quantities, sometimes kilograms, of protein are deposited in vital organs such as the kidney, heart and liver. In each of these diseases, a single protein undergoes a structural transition, often resulting in the formation of thread-like aggregates known as amyloid fibrils. Many of these diseases are linked to the ageing process, and as a large fraction of the world's population lives to ages unprecedented in human history, these diseases are emerging as among the most feared and debilitating in the modern world. In recent years, much research has focused on understanding what causes proteins to misfold and form amyloid structures, and on the specific mechanism by which such transitions occur. Nevertheless, as a result of structural heterogeneity, low populations and a transient nature, obtaining detailed information about this process has presented a formidable challenge. The primary objective of this study is to elucidate structural information of the different species that are populated along the aggregation pathway of human lysozyme. As well as being associated with a systemic amyloid disorder, lysozyme is one of the most highly studied of all proteins providing a unique opportunity to probe the difference between normal and aberrant behaviour at atomic resolution. By studying species populated under fibril forming conditions, we will be able to begin to understand not only the structures of intermediate species, but also the dynamics of the conversion between the different states involved in fibril formation. These studies should generate a sufficiently profound understanding of the distinctive differences between species involved in normal and aberrant folding behaviour to contribute significantly to the identification of novel strategies through which rational therapeutic intervention could lead to prevention or treatment, not just of this specific disease, but also perhaps the entire family of protein misfolding disorders.